US Pharm. 2006;10:57-64.

Female sexual dysfunction (FSD) is a complex and often misunderstood disorder. Though more prevalent in postmenopausal females due to an age-related decline of hormones (primarily estrogen), FSD also occurs in perimenopausal and premenopausal women. According to a 1999 study, sexual dysfunction was more prevalent in women than in men, affecting about 43% of women who participated in the study.1,2 One theory postulates that vaginal surgery may have an effect on female sexual function, although no definitive conclusion has been reached.3 Additionally, medications are a cause of sexual dysfunction; the antidepressant class is a major causative factor.1,4

Definition
Participants in the 1998 International Consensus Development Conference created a classification system for FSD that has four broad categories: orgasmic disorder, sexual arousal disorder, sexual desire disorder, and sexual pain disorder. Other classification systems have noted more types of disorders. For instance, according to the Report of the International Consensus Development Conference on Female Sexual Dysfunction, the condition may consist of seven or more disorders. Subsets of the sexual dysfunction category include physical, physiological, and psychological symptoms. FSD may include any of the following disorders: hypoactive sexual desire disorder (chronic lack of interest in sexual activity), sexual aversion disorder (persistent or recurrent phobic avoidance of sexual contact with a partner), female sexual arousal disorder (FSAD; persistent or recurrent inability to attain or maintain sexual excitement), orgasmic disorder (chronic difficulty in attaining orgasm following sufficient arousal), dyspareunia (pain during intercourse), vaginismus (involuntary vaginal spasms that interfere with penetration), and noncoital sexual pain (genital pain following stimulation during foreplay). The first four disorders must cause the woman distress to qualify as FSD. In addition to the aforementioned disorders, there are also conditions, procedures, and drugs that can affect sexual responses in women. 1,5

Data collected from a Kinsey Institute study in 2000 indicate that both emotional health and personal relationship factors are more important for a woman's sexual satisfaction than is achieving an orgasm, which men most consider the key factor.6

Treatment
Several different drugs are being studied as treatments for FSD. See Table 1 for information on drugs, dosages, and side effects.

Phosphodiesterase Type-5 Inhibitors: Sildenafil citrate (Viagra/Pfizer), a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5), was the first of a class of three oral agents to be developed and approved by the FDA for the treatment of erectile dysfunction (ED) in men. The mechanism of action of this class involves the active inhibition of the phosphodiesterase enzyme and smooth muscle relaxation in the penis.

Due to its tremendous success in the treatment of ED, sildenafil has also been studied to determine its benefit/efficacy in the treatment of FSD.5,7 Berman et al. conducted a 12-week, randomized, double-blind study evaluating the efficacy and safety of sildenafil in 202 spontaneously menopausal or surgically postmenopausal women with female sexual arousal disorder (FSAD) of at least six months in duration. Subjects received either sildenafil in a dosage range of 25 to 100 mg or placebo in addition to the estrogen and/or androgen replacement therapy they were previously taking. The six-item Female Intervention Efficacy Index was used to determine efficacy. The primary end points of the study were whether there was increased genital sensation during intercourse or stimulation and increased satisfaction with intercourse and/or foreplay. Compared to placebo, treatment with sildenafil was associated with a significant improvement in both end points and in increases in vaginal lubrication, ability to have a vaginal orgasm, and overall sexual experience. The most frequently reported adverse events were headache, flushing, rhinitis, nausea, vomiting, and visual disturbances.5

A randomized, double-blind, placebo-controlled, three-way crossover study evaluating the efficacy of sildenafil in 53 premenopausal women with FSD was also conducted.8 Treatment consisted of three four-week periods with patients receiving either sildenafil 25 mg, sildenafil 50 mg, or placebo. Patients reported significant improvements in both arousal and orgasm and other sexual activity scores, including frequency of intercourse, frequency of sexual fantasies, satisfaction with frequency, and enjoyment, compared with placebo and baseline. Reported adverse events were vision problems, fear of undesired effects, and headache. Fourteen cases of irreversible vision loss were reported in men who had taken the drug within the past 36 hours.9

Other studies have examined the use of sildenafil for treatment of FSD due to spinal cord injury, multiple sclerosis (MS), and psychotropic-induced sexual dysfunctions (PISD). In patients with spinal cord injury, sildenafil was associated with significant increases in subjective arousal with visual and manual stimulation. In those with FSD due to MS, significant improvements in sensation and lubrication were noted. In those with PISD, improvements were shown in overall sexual satisfaction.8

Though the use of sildenafil has been studied for the treatment of sexual dysfunction in women, Pfizer reports that it does not have a plan to seek FDA approval for this new indication.10

Approved by the FDA in August 2003 for the treatment of ED, vardenafil, the second approved oral PDE-5 inhibitor, has similar duration of action to sildenafil but is said to be more potent and selective biochemically. The side-effect profile of both drugs is also similar. To date, no human studies have been conducted to test the drug's use in the treatment of FSD; only animal models have been used.11-13

Tadalafil, the newest agent approved by the FDA in November 2003 for the treatment of ED, is a long-acting PDE-5 inhibitor shown to be effective for up to 36 hours in the majority of men. The drug has also been shown to be well tolerated and without serious side effects. A Medline search did not find any studies of the drug used for treatment of FSD. 12,14-16

Alprostadil: Used in the diagnosis and treatment of ED, alprostadil USP, prostaglandin E1, is commercially available as Caverject Injection, Edex Injection, and MUSE Pellet. Four double-blind, placebo-controlled, phase II trials have shown that alprostadil topical cream is efficacious and well tolerated in men with mild to severe symptoms of ED and in those undergoing treatment for cardiovascular diseases and diabetes. It is now a potential first-choice alternative for ED in patients who cannot tolerate, are nonresponsive to, or are unaccepting of therapy with PDE-5 inhibitors.17

As with the PDE-5 inhibitors, the success of alprostadil in the treatment of ED has led to studies of its use to treat FSD. For instance, the efficacy and safety of topical alprostadil cream for the treatment of FSAD was studied in a double-blind, multicenter, randomized, placebo-controlled trial. The study involved 94 women presenting with FSAD for at least six months. Patients used 10 premeasured alprostadil doses of 500, 1,000, or 1,500 mcg or a placebo cream for topical application to the vulvar area prior to intercourse. The arousal success rate was measured by responses to the Female Sexual Encounter Profile. Results indicated that the success rate was highest in the 1,000-mcg group and lowest in the 500-mcg group. Most side effects reported were mild to moderate and local in nature.18

A second study involving 78 women with FSD who were either postmenopausal or had undergone a hysterectomy and bilateral oophorectomy showed that treatment with topical alprostadil was well tolerated, with no reports of serious side effects. The women were randomized to receive either alprostadil solution 100 or 400 mcg or placebo. The solution was applied to the clitoris and allowed to spread to surrounding tissues. Both doses resulted in an increase in vulvar erythema and edema, suggesting an increase in blood flow.19

A smaller pilot study involving eight patients has also shown that alprostadil is effective in patients with FSD. Patients were administered a single intravaginal dose, followed by escalating intravaginal doses of the active drug or placebo at two-week intervals. While the results did indicate enhancement of subjective and physiological arousal during visual sexual stimulation, researchers concluded that further investigation must be done before a definitive conclusion can be reached.20 Researchers are also developing an alprostadil formulation to be applied to the vulva.

A combination of alprostadil cream and the adrenoreceptor agonist phentolamine has also been studied, but no conclusion has been reached regarding efficacy or safety.

Dronabinol: Used primarily when conventional antiemetics fail to relieve the nausea and vomiting associated with cancer chemotherapy and to stimulate appetite in patients with AIDS-related anorexia, dronabinol has also been studied for treatment of FSD. The active ingredient in dronabinol is tetrahydrocannabinol, a substance known to have sexually enhancing effects.

A case report involving a 43-year-old married African-American woman with a history of bipolar disorder showed that the use of dronabinol one hour before sex improved the patient's sexual function in the areas of libido, arousal, lubrication, orgasm, and the overall quality of her sex life. The patient reported that she had previously been noncompliant with her psychotropic medications due to the sexual dysfunction caused by them. 21 Due to its potential for abuse, dronabinol should be used only as prescribed and not overused. Though the use of dronabinol in this case report showed positive effects in the treatment of FSD, it is not approved by the FDA for this indication.

Granisetron: According to a presentation at the Canadian Psychiatric Association 53rd Annual Meeting, depressed women are more likely to have sexual dysfunction than are depressed men.22 Granisetron, a 5-HT3 receptor antagonist used for the prophylaxis and treatment of chemotherapy-induced emesis, has also been studied as a possible treatment for antidepressant-induced sexual dysfunction (AISD) in women.

A randomized, double-blind, placebo-controlled, two-week pilot study examined the use of granisetron in the treatment of FSD due to antidepressant use. Twelve women were assigned to either granisetron or placebo. Results indicated that there was no statistical difference between the two groups; therefore, the study did not produce evidence supporting the usefulness of granisetron in AISD.23

Melanocortin Agonists:Palatin Technologies, Inc. has developed PT-141, the first in a new class of therapies called melanocortin agonists. The mechanism of action primarily involves the central nervous system rather than direct action on the vascular system.24

PT-141 has been studied in men and women. The intranasally administered medication, which is not contraindicated for use in patients taking nitrates, has shown favorable results in two clinical trials involving women. A phase I study examined the drug in 32 premenopausal women without FSD; a phase IIA study involved 18 premenopausal women diagnosed with FSD. Compared to placebo, PT-141 led to a significant increase in sexual desire and genital arousal.25 A phase IIB at-home study in women is ongoing.

Hormones: Androgen deficiency has long been considered a cause of sexual dysfunction in men. Testosterone, dehydroepiandrosterone, androstenedione, and androgen/estrogen combinations have maintained their place in therapy.

Estrogen and testosterone levels may decrease by 30% to 50% in women who have undergone either natural or surgically induced menopause. Increasing testosterone levels in these patients may reduce sexual dysfunction. The efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women was studied in a 24-week, randomized, double-blind, placebo-controlled trial. Four hundred forty-seven women were randomized to receive placebo or testosterone patches in doses of 150, 300, or 450 mcg/day twice weekly. Women receiving the 300-mcg/day testosterone patch reported both an increase in sexual desire and frequency of satisfying sexual activity.26 A second trial involving 533 women who had previously undergone a hysterectomy and bilateral oophorectomy showed similar results. Treatment with the testosterone patch significantly improved sexual activity and sexual desire and decreased personal distress.27 Androgenic side effects, including acne and hair growth, were mild in both trials. The FDA has deemed the testosterone patch efficacious but has requested data from more long-term studies. Decreased vaginal lubrication and resultant painful intercourse have also been cited by many women as a deterrent to sexual activity. The pharmacist can recommend water-based OTC vaginal lubricants to resolve this problem.

Dopamine Receptor Agonists: Nastech Pharmaceutical Company has developed an intranasal formulation of apomorphine for the treatment of male and female sexual dysfunction.4 Due to relatively positive clinical data, the company plans to obtain regulatory guidance from the FDA to permit development, approval, and marketing of the product for sexual dysfunction.28

Likewise, patients who have been prescribed bupropion for treatment of selective serotonin reuptake inhibitor-induced sexual dysfunction have reported an increase in libido.4

Herbals and Supplements:The efficacy and safety of Zestra for Women, a feminine massage oil containing natural botanical ingredients such as evening primrose oil and vitamin E, was tested in 20 women, 10 with and 10 without sexual dysfunction. The product improved sexual function in normal women and in those with FSAD, under conditions of home use.29

ArginMax, a nutritional supplement containing the nitric oxide facilitator L-arginine, in combination with ginseng, gingko, damiama, multivitamins, and other minerals, has also been studied for use in the treatment of FSD. While positive effects were reported, further study is necessary. Another combination of L-arginine and yohimbine patented by NitroMed has undergone phase II trials, but to date, no further research has been undertaken.4

Medical Devices:Some schools of thought postulate that FSD may also be related to a decrease in blood flow to the clitoris or vagina, with an etiology similar to that of ED. A vacuum pump device manufactured under the name Eros Clitoral Therapy has been designed to enhance clitoral engorgement and increase blood flow to both the clitoris and the vagina. In a study involving 13 women with diabetes who were instructed to use the device at least four times a week as part of a tissue-conditioning routine and at least twice weekly before attempting to engage in intercourse, significant benefit in sensation, lubrication, orgasm, and sexual satisfaction was reported after only one month of therapy. Even greater benefit was shown after three months.30 Eros is the only FDA-approved device for use in female arousal disorders.

Conclusion
Since Viagra exploded onto the marketplace as a treatment for ED in men, this drug and others in its class have been studied for the treatment of FSD. Most research results have indicated that further study in larger female patient populations is necessary prior to the FDA approval of medications in this class or others to treat the condition. While hormonal therapy in the form of estrogens and androgens will continue to be a mainstay of FSD treatment, the discovery of the melanocortin-agonist therapeutic class may lead to new treatment of sexual dysfunction in both sexes.

Medical devices such as Eros Therapy serve as a viable alternative to drug therapy in the treatment of FSD. Although the research involved has been conducted only in women with diabetes, the device may also be used to treat nondiabetic women.

The subjectivity of FSD compared to the objectivity of ED is a definite challenge to finding a new treatment, whether in the form of a newly approved indication or a newly developed therapeutic entity.

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